Balanced crystalloid solution versus saline in deceased donor kidney transplantation (BEST-Fluids): a pragmatic, double-blind, randomised, controlled trial.

BACKGROUND: Delayed graft function (DGF) is a major adverse complication of deceased donor kidney transplantation. Intravenous fluids are routinely given to patients receiving a transplant to maintain intravascular volume and optimise graft function. Saline (0·9% sodium chloride) is widely used but might increase the risk of DGF due to its high chloride content. We aimed to test our hypothesis that using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce the incidence of DGF. METHODS: BEST-Fluids was a pragmatic, registry-embedded, multicentre, double-blind, randomised, controlled trial at 16 hospitals in Australia and New Zealand. Adults and children of any age receiving a deceased donor kidney transplant were eligible; those receiving a multi-organ transplant or weighing less than 20 kg were excluded. Participants were randomly assigned (1:1) using an adaptive minimisation algorithm to intravenous balanced crystalloid solution (Plasma-Lyte 148) or saline during surgery and up until 48 h after transplantation. Trial fluids were supplied in identical bags and clinicians determined the fluid volume, rate, and time of discontinuation. The primary outcome was DGF, defined as receiving dialysis within 7 days after transplantation. All participants who consented and received a transplant were included in the intention-to-treat analysis of the primary outcome. Safety was analysed in all randomly assigned eligible participants who commenced surgery and received trial fluids, whether or not they received a transplant. This study is registered with Australian New Zealand Clinical Trials Registry, (ACTRN12617000358347), and ClinicalTrials.gov (NCT03829488). FINDINGS: Between Jan 26, 2018, and Aug 10, 2020, 808 participants were randomly assigned to balanced crystalloid (n=404) or saline (n=404) and received a transplant (512 [63%] were male and 296 [37%] were female). One participant in the saline group withdrew before 7 days and was excluded, leaving 404 participants in the balanced crystalloid group and 403 in the saline group that were included in the primary analysis. DGF occurred in 121 (30%) of 404 participants in the balanced crystalloid group versus 160 (40%) of 403 in the saline group (adjusted relative risk 0·74 [95% CI 0·66 to 0·84; p<0·0001]; adjusted risk difference 10·1% [95% CI 3·5 to 16·6]). In the safety analysis, numbers of investigator-reported serious adverse events were similar in both groups, being reported in three (<1%) of 406 participants in the balanced crystalloid group versus five (1%) of 409 participants in the saline group (adjusted risk difference -0·5%, 95% CI -1·8 to 0·9; p=0·48). INTERPRETATION: Among patients receiving a deceased donor kidney transplant, intravenous fluid therapy with balanced crystalloid solution reduced the incidence of DGF compared with saline. Balanced crystalloid solution should be the standard-of-care intravenous fluid used in deceased donor kidney transplantation. FUNDING: Medical Research Future Fund and National Health and Medical Research Council (Australia), Health Research Council (New Zealand), Royal Australasian College of Physicians, and Baxter.

Defining causes of death-censored kidney allograft failure: A 5-year multicentre ANZDATA and clinical cross-sectional study.

AIM: Determining specific causes of allograft failure allows a focus on understanding and treating these conditions. Previous studies highlight chronic antibody-mediated rejection as a leading cause of late allograft failure. We sought to define causes of allograft failure in a large cohort of kidney transplant recipients across multiple centres in Australia and New Zealand, including cases previously attributed to chronic allograft nephropathy (CAN). METHODS: All death-censored allograft failures at 9 participating centres between 1 January 2014 to 31 December 2018 were included. Available clinical and biopsy data were reviewed and the "most likely" cause assigned. RESULTS: There were 642 death-censored allograft failures in the study period. Of these, 495 (77.1%) had an informative biopsy performed a median of 13.4 months (IQR 2.5-39.1 months) prior to allograft failure. Rejection of any type was the leading cause of allograft failure (47.5%), comprised chiefly of chronic antibody-mediated rejection (37.4%) and chronic T-cell mediated rejection (6.4%). Other leading causes were undifferentiated interstitial fibrosis and tubular atrophy (10.8%), late medical and surgical complications (8.1%) and recurrent or de novo glomerulonephritis (7.0%). Polyoma viral nephropathy and calcineurin inhibitor toxicity each contributed to <2%. Causes of allograft failure previously attributed to CAN (n = 419, 65.3%) had a similar distribution to the overall cohort, with 43.9% attributed to chronic antibody-mediated rejection. CONCLUSION: To prolong allograft survival, improved strategies are needed to curtail alloimmune responses. Greater understanding of the causes of undifferentiated interstitial fibrosis and tubular atrophy and potential treatments would also be of considerable benefit.

Invasive Management and Outcomes in Acute Coronary Syndromes and Chronic Kidney Disease (ANZACS-QI 70).

AIMS: Guidelines recommend management with an invasive coronary angiogram in acute coronary syndromes (ACS), but most studies excluded patients with advanced chronic kidney disease (CKD). Our aims were to describe, in a comprehensive ACS cohort, the incidence of CKD, coronary angiography utilisation and outcomes, according to CKD stage. METHODS: National datasets were used to identify hospitalised ACS patients (2013 to 2018) in the Northern region of New Zealand. CKD stage was obtained from a linked laboratory dataset. Outcomes included all-cause and cause-specific mortality, and non-fatal myocardial infarction, heart failure and stroke. RESULTS: Thirty-eight percent (38%) of the 23,432 ACS patients had CKD stage 3 or higher: 2,403 (10%) had stages 4/5 CKD. Overall 61% received coronary angiography. Compared with normal renal function the adjusted rate of coronary angiography was lower in CKD stage 3b (RR 0.75, 95% confidence intervals [CIs] 0.69, 0.82) and stages 4/5 without dialysis (RR 0.41, 95% CIs 0.36, 0.46), but similar for those on dialysis (RR 0.89, 95% CIs 0.77, 1.02). All-cause mortality (mean follow-up 3.2 years) increased with CKD stage from 8% (normal kidney function) to 69% (stages 4/5 CKD without dialysis). Compared with coronary angiography, the adjusted all-cause and CVD mortality risks were higher in those without coronary angiography, except for those on dialysis, where these risks converged. CONCLUSIONS: Invasive management fell below an eGFR of 45 mL/min (≤ stage 3b), and nearly half of all deaths occurred in these patients. Clinical trials are needed to assess the role of invasive management in ACS and advanced CKD.

Interactions Between Donor Age and 12-Month Estimated Glomerular Filtration Rate on Allograft and Patient Outcomes After Kidney Transplantation.

Reduced estimated glomerular filtration rate (eGFR) at 12-months after kidney transplantation is associated with increased risk of allograft loss, but it is uncertain whether donor age and types modify this relationship. Using Australia and New Zealand registry data, multivariable Cox proportional modelling was used to examine the interactive effects between donor age, types and 12-month eGFR on overall allograft loss. We included 11,095 recipients (4,423 received live-donors). Recipients with lowest 12-month eGFR (<30 ml/min/1.73 m2) experienced the greatest risk of allograft loss, with adjusted HR [95% CI) of 2.65 [2.38-2.95] compared to eGFR of 30-60 ml/min/1.73 m2; whereas the adjusted HR for highest eGFR (>60 ml/min/1.73 m2) was 0.67 [0.62-0.74]. The association of 12-month eGFR and allograft loss was modified by donor age (but not donor types) where a higher risk of allograft loss in recipients with lower compared with higher 12-month eGFR being most pronounced in the younger donor age groups (p < 0.01). Recipients with eGFR <30 ml/min/1.73 m2 12-months after transplantation experienced ≥2.5-fold increased risk of overall allograft loss compared to those with eGFR of >60 ml/min/1.73 m2, and the magnitude of the increased risk is most marked among recipients with younger donors. Careful deliberation of other factors including donor age when considering eGFR as a surrogate for clinical endpoints is warranted.

Impact of chronic kidney disease on mortality and cardiovascular outcomes after acute coronary syndrome: A nationwide data linkage study (ANZACS-QI 44).

AIMS: Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease (CVD). We examined the characteristics, management and outcomes of patients with CKD in the All New Zealand Acute Coronary Syndrome Quality Improvement (ANZACS-QI) national registry. METHODS: The cohort comprised New Zealand (NZ) patients with an acute coronary syndrome undergoing coronary angiography between January 2013 and December 2016. Patients were categorized according to their stage of CKD. Outcomes included all-cause and cause-specific mortality and hospitalization with myocardial infarction (MI), stroke and major bleeding. RESULTS: Of the 20 604 patients, 20.3% had normal renal function, with 53.3%, 23.3%, 1.7% and 1.4% having CKD stages 2, 3, 4 and 5 CKD, respectively. Patients with severe CKD were more likely to be Maori or Pacific and live in an area with greater socioeconomic deprivation. Death, recurrent MI or stroke, and major bleeding all increased incrementally with each worsening stage of CKD severity. Compared with those with normal renal function, patients with stage 5 CKD had a much higher all-cause (hazard ratio [HR] 16.41, 95% CI 13.06-20.61), cardiovascular (HR 16.38, 95% CI 12.17-22.04) and non-cardiovascular mortality (HR 13.66 9, 95% CI.56-19.51). In addition, patients with stage 5 CKD were at a higher risk of recurrent MI or stroke (HR 4.73, 95% CI 3.86-5.80) and bleeding (HR 5.84, 95% CI 4.39-7.76). CONCLUSION: CKD was associated with increased mortality and a high incidence of morbidity in patients undergoing coronary angiography in New Zealand. Initiatives to understand and improve outcomes in this group of patients are urgently needed.

Carvedilol and Cardiac Biomarkers in Dialysis Patients: Secondary Analysis of a Randomized Controlled Trial.

BACKGROUND/AIMS: Cardiac biomarkers are associated with cardiac abnormalities and adverse outcomes in dialysis patients. Our aim was to report the effect of the beta-blocker carvedilol on cardiac biomarkers in adult dialysis patients. METHODS: The Beta-Blocker to Lower Cardiovascular Dialysis Events Feasibility Study was a randomized controlled trial comparing carvedilol to placebo. Serum and plasma were collected before the run-in, then 6 and 12 months post-randomization to measure B-type Natriuretic Peptide (BNP), N-terminal BNP (NT-ProBNP), high-sensitivity cardiac troponins I (hs-TnI) and T (hs-TnT), and galectin-3. Left ventricular global longitudinal strain (GLS) was measured by echocardiography at baseline. RESULTS: Seventy-two participants were recruited of whom 49 completed the run-in and were randomized to carvedilol (n=26) or placebo (n=23). Baseline echocardiography demonstrated median (inter-quartile range) GLS of -14.27% (-16.63 to -11.93). NTproBNP and hs-TnT correlated with GLS (Spearman's rho=0.34 [p=0.018] and rho=0.28 [p=0.049], respectively). Median change scores from baseline to 12 months did not differ significantly between participants with complete biomarker data randomized to carvedilol (n=15) or placebo (n=16) for any biomarkers. CONCLUSIONS: NT-proBNP and hs-TnT were associated with GLS. However, changes in levels of the biomarkers from baseline to 12 months were not different between groups randomized to carvedilol and placebo.

The ß-Blocker to Lower Cardiovascular Dialysis Events (BLOCADE) Feasibility Study: A Randomized Controlled Trial.

BACKGROUND: ß-Blocking agents reduce cardiovascular mortality in patients with heart disease, but their potential benefit in dialysis patients is unclear. We aimed to determine the feasibility of a randomized controlled trial (RCT). STUDY DESIGN: Pilot RCT. SETTING & PARTICIPANTS: Patients who received dialysis for 3 or more months and were 50 years or older (or ≥18 years with diabetes or cardiovascular disease) were recruited from 11 sites in Australia and New Zealand. We aimed to recruit 150 participants. INTERVENTION: After a 6-week run-in with the ß-blocker carvedilol, we randomly assigned participants to treatment with carvedilol or placebo for 12 months. OUTCOMES & MEASUREMENTS: The prespecified primary outcome was the proportion of participants who tolerated carvedilol, 6.25mg, twice daily during the run-in period. After randomization, we report participant withdrawal and the incidence of intradialytic hypotension (IDH). RESULTS: Of 1,443 patients screened, 354 were eligible, 91 consented, and 72 entered the run-in stage. 49 of 72 run-in participants (68%; 95% CI, 57%-79%) achieved the primary outcome. 5 of the 23 withdrawals from run-in were attributable to bradycardia or hypotension. After randomization, 10 of 26 allocated to carvedilol and 4 of 23 allocated to placebo withdrew. 4 participants randomly assigned to carvedilol withdrew because of bradycardia or hypotension. Overall, there were 4 IDH events per 100 hemodialysis sessions; in participants allocated to carvedilol versus placebo, respectively, there were 7 versus 2 IDH events per 100 hemodialysis sessions (P=0.1) in the 2 weeks immediately following a dose increase and 4 versus 3 IDH events per 100 hemodialysis sessions after no dose increase (P=0.7). LIMITATIONS: Unable to recruit planned sample size. CONCLUSIONS: Recruiting patients receiving dialysis to an RCT of ß-blocker versus placebo will prove challenging. Possible solutions include international collaboration and exploring novel trial designs such as a registry-based RCT.

Long-term outcomes for primary glomerulonephritis: New Zealand Glomerulonephritis Study.

AIMS: Due to the paucity of studies focusing on primary glomerulonephritis, the second commonest cause of end-stage-kidney-disease in most of the developed world, we sought to review outcomes of these renal pathologies. METHODS: We reviewed renal outcomes and mortality for primary glomerulonephritis patients enrolled in the New Zealand Glomerulonephritis Study between 1972 and 1983. RESULTS: There were 765 patients with median follow-up of 30 years (range 0.1-42 years). They were predominantly New Zealand European, male and hypertensive. Poor renal outcomes and increased mortality were associated with hypertension, heavy proteinuria, impaired renal function and older age at diagnosis. Ethnicity was not significantly associated with progression to end-stage-kidney-disease although NZ Maori patients were at significantly increased risk of death. Patients with rapidly progressive glomerulonephritis had the highest risk of reaching end-stage-kidney-disease while the cumulative incidence of end-stage-kidney-disease was 20% and 30% for those with immunoglobulin-A nephropathy and membranous nephropathy respectively. Mortality risk was high for patients with rapidly progressive glomerulonephritis and anti-glomerular basement membrane disease. The era of diagnosis did not have much effect on outcomes except for patients with focal segmental glomerulosclerosis or immunoglobulin A nephropathy but this could be type II error. CONCLUSION: We report one of the longest follow-up studies on biopsy-proven glomerulonephritides. Age, hypertension, and severity of chronic kidney disease at diagnosis were strong predictors of the development of end-stage-kidney-disease and death. The specific renal pathology had a profound impact upon prognosis and therefore should continue to drive efforts to find targeted therapeutic options for these glomerulonephritides.

The rationale and design of the Beta-blocker to LOwer CArdiovascular Dialysis Events (BLOCADE) Feasibility Study.

AIMS: The Beta-blocker to LOwer CArdiovascular Dialysis Events (BLOCADE) Feasibility Study aims to determine the feasibility of a large-scale randomized controlled trial with clinical endpoints comparing the beta-blocking agent carvedilol with placebo in patients receiving dialysis. METHODS: The BLOCADE Feasibility Study is a randomized, double-blind, placebo-controlled, parallel group feasibility study comparing the beta-blocking agent carvedilol with placebo. Patients receiving dialysis for ≥3 months and who are aged ≥50 years, or who are ≥18 years and have diabetes or cardiovascular disease, were eligible. The primary outcome was the proportion of participants who complete a 6-week run-in phase in which all participants received carvedilol titrated from 3.125 mg twice daily to 6.25 mg twice daily. Other measures included how many patients are screened, the proportion recruited, the overall recruitment rate, the proportion of participants who remain on study drug for 12 months and the incidence of intra-dialytic hypotension while on randomized treatment. RESULTS: The BLOCADE Feasibility Study commenced recruiting in May 2011 and involves 11 sites in Australia and New Zealand. CONCLUSIONS: The BLOCADE Feasibility Study will inform the design of a larger clinical endpoint study to determine whether beta-blocking agents provide benefit to patients receiving dialysis, and define whether such a study is feasible.

Challenges in blood pressure measurement in patients treated with maintenance hemodialysis.

The association between blood pressure and cardiovascular outcomes in patients undergoing hemodialysis remains controversial. This may relate in part to the technique and device used and the timing of the blood pressure measurement in relation to the hemodialysis procedure. Emerging evidence indicates that standardized hemodialysis unit blood pressure measurements or measurements obtained at home, either by the patient or using an ambulatory blood pressure monitor, may offer advantages over routine hemodialysis unit blood pressure measurements for determining cardiovascular risk and treatment. This review discusses the available evidence and implications for clinicians and clinical trials.

Baseline Characteristics and Representativeness of Participants in the BEST-Fluids Trial: A Randomized Trial of Balanced Crystalloid Solution Versus Saline in Deceased Donor Kidney Transplantation.

Delayed graft function (DGF) is a major complication of deceased donor kidney transplantation. Saline (0.9% sodium chloride) is a commonly used intravenous fluid in transplantation but may increase the risk of DGF because of its high chloride content. Better Evidence for Selecting Transplant Fluids (BEST-Fluids), a pragmatic, registry-based, double-blind, randomized trial, sought to determine whether using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce DGF. We sought to evaluate the generalizability of the trial cohort by reporting the baseline characteristics and representativeness of the trial participants in detail. Methods: We compared the characteristics of BEST-Fluids participants with those of a contemporary cohort of deceased donor kidney transplant recipients in Australia and New Zealand using data from the Australia and New Zealand Dialysis and Transplant Registry. To explore potential international differences, we compared trial participants with a cohort of transplant recipients in the United States using data from the Scientific Registry of Transplant Recipients. Results: During the trial recruitment period, 2373 deceased donor kidney transplants were performed in Australia and New Zealand; 2178 were eligible' and 808 were enrolled in BEST-Fluids. Overall, trial participants and nonparticipants were similar at baseline. Trial participants had more coronary artery disease (standardized difference [d] = 0.09; P = 0.03), longer dialysis duration (d = 0.18, P < 0.001), and fewer hypertensive (d = -0.11, P = 0.03) and circulatory death (d = -0.14, P < 0.01) donors than nonparticipants. Most key characteristics were similar between trial participants and US recipients, with moderate differences (|d| ≥ 0.2; all P < 0.001) in kidney failure cause, diabetes, dialysis duration, ischemic time, and several donor risk predictors, likely reflecting underlying population differences. Conclusions: BEST-Fluids participants had more comorbidities and received slightly fewer high-risk deceased donor kidneys but were otherwise representative of Australian and New Zealand transplant recipients and were generally similar to US recipients. The trial results should be broadly applicable to deceased donor kidney transplantation practice worldwide.

Review: metformin: potential benefits and use in chronic kidney disease.

Diabetes mellitus is the commonest cause of end-stage renal failure in both Australia and New Zealand. In addition, the burden of diabetes is prominent in those with chronic kidney disease who have not yet reached the requirement for renal replacement therapy. While diabetes is associated with a higher incidence of mortality and morbidity in all populations studied with kidney disease, little is known about optimal treatment strategies for hyperglycaemia and the effects of glycaemic treatment in this large group of patients. Metformin is recommended as the drug of first choice in patients diagnosed with type 2 diabetes in the USA, Europe and Australia. There are potential survival benefits associated with the use of metformin in additional to recent studies suggesting benefits in respect to cardiovascular outcomes and metabolic parameters. The use of metformin has been limited in patients with renal disease because of the perceived risk of lactic acidosis; however, it is likely that use of this drug would be beneficial in many with chronic kidney disease. Thus the potential benefits and harms of metformin are outlined in this review with suggestions for its clinical use in those with kidney disease.

Increased Peripheral Blood Heteroplasmy of the mt.3243A>G Mutation Is Associated with Earlier End-Stage Kidney Disease: A Case Report and Review of the Literature.

The mitochondrial DNA mutation mt.3243A>G is most commonly associated with maternally inherited diabetes and deafness (MIM 52,000), but it has protean phenotypes including renal disease due to focal segmental glomerulosclerosis. We describe monozygotic twins who both harboured this mutation and developed ESRD. Although otherwise genetically identical, the twins differed in their peripheral blood leucocyte levels of circulating mt.3243A>G heteroplasmy: 20 versus 10%, when assessed at 42 years of age. The twin with the higher heteroplasmy load developed end-stage kidney disease 15 years earlier than her sister. A review of the published literature supports a relationship between heteroplasmy level and the age at the development of the end stage of renal failure in patients with mt.3243A>G-related kidney disease.

KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation.

The 2020 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation is intended to assist health care professionals worldwide who evaluate and manage potential candidates for deceased or living donor kidney transplantation. This guideline addresses general candidacy issues such as access to transplantation, patient demographic and health status factors, and immunological and psychosocial assessment. The roles of various risk factors and comorbid conditions governing an individual's suitability for transplantation such as adherence, tobacco use, diabetes, obesity, perioperative issues, causes of kidney failure, infections, malignancy, pulmonary disease, cardiac and peripheral arterial disease, neurologic disease, gastrointestinal and liver disease, hematologic disease, and bone and mineral disorder are also addressed. This guideline provides recommendations for evaluation of individual aspects of a candidate's profile such that each risk factor and comorbidity are considered separately. The goal is to assist the clinical team to assimilate all data relevant to an individual, consider this within their local health context, and make an overall judgment on candidacy for transplantation. The guideline development process followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Guideline recommendations are primarily based on systematic reviews of relevant studies and our assessment of the quality of that evidence, and the strengths of recommendations are provided. Limitations of the evidence are discussed with differences from previous guidelines noted and suggestions for future research are also provided.

Summary of the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation.

The 2020 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation is intended to assist health care professionals worldwide who evaluate and manage potential candidates for deceased or living donor kidney transplantation. This guideline addresses general candidacy issues such as access to transplantation, patient demographic and health status factors, immunological and psychosocial assessment. The roles of various risk factors and comorbid conditions governing an individual's suitability for transplantation such as adherence, tobacco use, diabetes, obesity, perioperative issues, causes of kidney failure, infections, malignancy, pulmonary disease, cardiac and peripheral arterial disease, neurologic disease, gastrointestinal and liver disease, hematologic disease, and bone and mineral disorder are also addressed. This guideline provides recommendations for evaluation of individual aspects of a candidate's profile such that each risk factor and comorbidity are considered separately. The goal is to assist the clinical team to assimilate all data relevant to an individual, consider this within their local health context, and make an overall judgment on candidacy for transplantation. The guideline development process followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Guideline recommendations are primarily based on systematic reviews of relevant studies and our assessment of the quality of that evidence. The strengths of recommendations are provided in the full report. Limitations of the evidence are discussed with differences from previous guidelines noted and suggestions for future research are also provided.

Review article: Coronary artery stenoses: detection and revascularization in renal disease.

Cardiovascular events are markedly elevated in those with all degrees of renal impairment compared to the general population. There are well established guidelines in the general population for the management of coronary artery disease, however, similar guidelines have not been established in the renal population. This review examines the current published work on the detection of coronary artery stenoses in addition to summarizing the outcomes of revascularization in patients with kidney disease. Testing for coronary artery disease in the renal population most commonly occurs in dialysis patients as part of their assessment for renal transplantation. While a positive myocardial stress test for the detection of significant coronary artery stenoses is associated with an increased risk of cardiac events, there is no clear information currently showing that cardiovascular testing itself reduces the rate of adverse cardiac events after transplantation. Revascularization of coronary artery stenoses is associated with higher morbidity and mortality in all groups with kidney disease than in the general population, with the exception of renal transplant recipients where the mortality is likely to be similar to that of the general population. There appears to be a benefit in coronary artery bypass surgery compared to percutaneous intervention in those on dialysis and after renal transplant. Currently, there is little data to support coronary artery intervention prior to transplantation in those with asymptomatic coronary artery disease.

Australia and New Zealand Islets and Pancreas Transplant Registry Annual Report 2018-Pancreas Waiting List, Recipients, and Donors.

BACKGROUND: This is a synopsis of the registry report from the Australia and New Zealand islet and pancreas transplant registry. The full report is available at http://anziptr.org/reports/. METHODS: We report data for all solid organ pancreas transplant activity from inception in 1984 to end 2017. Islet-cell transplantation activity is reported elsewhere. Data analysis was performed using Stata software version 14 (StataCorp, College Station, TX). RESULTS: From 1984 to 2017 a total of 809 solid organ pancreas transplants have been performed in Australia and New Zealand, in 790 individuals. In 2017, 52 people received a pancreas transplant. By center, this was; Auckland (4), Monash (17), and Westmead (31). In 2017, 51 transplants were simultaneous pancreas kidney, whereas 1 was pancreas after kidney, and none were pancreas transplant alone. CONCLUSIONS: The number of pancreas transplants performed in Australia and New Zealand was slightly lower in 2017 but continues to increase over time.

Long-term outcomes of kidney transplant recipients with end-stage kidney disease attributed to presumed/advanced glomerulonephritis or unknown cause.

People with biopsy-proven glomerulonephritis (GN) as their cause of end-stage kidney disease (ESKD) who undergo kidney transplantation incur significant risk of recurrent GN-related graft failure, but the risk in recipients with ESKD where GN was suspected but not biopsy proven (presumed/advanced GN) and when the cause of ESKD is unknown remains uncertain. Using the Australia and New Zealand Dialysis and Transplant registry, we examined the associations between primary kidney transplant recipients whose ESKD was attributed to: 1) commonly-recurring GN (i.e. IgA nephropathy, membranoproliferative GN, focal segmental glomerulosclerosis and membranous GN), 2) presumed/advanced GN, and 3) cause of ESKD unknown (uESKD) and GN-related graft failure using adjusted competing risk models. Of 5258 recipients followed for a median of 8 years, 3539 (67.3%) had commonly-recurring GN, 1195 (22.7%) presumed/advanced GN, and 524 (10.0%) uESKD. Compared to recipients with commonly-recurring GN, recipients with presumed/advanced GN or uESKD experienced a low incidence of GN-related graft failure (<1%) and a lower hazard of GN-related graft failure (adjusted sub-distribution hazard ratio [HR] 0.28 [95%CI 0.15-0.54,p < 0.001] and 0.20 [95%CI 0.06-0.64,p = 0.007], respectively). People with ESKD attributed to either presumed/advanced GN or unknown cause face a very low risk of graft failure secondary to GN recurrence after transplantation.

Epithelial-to-mesenchymal transition of human proximal tubular epithelial cells: effects of rapamycin, mycophenolate, cyclosporin, azathioprine, and methylprednisolone.

Epithelial-to-mesenchymal transition (EMT) of renal proximal tubular epithelial cells (PTEC) into myofibroblasts is an important step in the pathogenesis of chronic allograft nephropathy. The effects of commonly used immunosuppressives in renal transplantation on EMT are not known. PTEC were cultured in transforming growth factor-beta to induce EMT. The effects of the immunosuppressives on cell morphology and alpha-smooth muscle actin were studied by phase contrast microscopy, immunocytochemistry, and western blotting. The effects on versican were studied by [S] labeling and polyacrylamide gel electrophoresis. Rapamycin and mycophenolate mofetil (MMF) prevented EMT and moreover returned myofibroblasts to PTEC morphology. These immunosuppressives also reduced versican production by both PTEC and myofibroblasts. Cyclosporine A, azathioprine, and methylprednisolone were less effective than rapamycin and MMF. Moreover, these immunosuppressives did not decrease versican. Rapamycin and MMF have a greater inhibitory effect on EMT in vitro than older immunosuppressives and may result in less fibrosis and a better long-term allograft survival.

Long-term outcomes of kidney transplantation in people with type 2 diabetes: a population cohort study.

BACKGROUND: Overall survival for younger patients with type 2 diabetes without kidney disease has improved substantially over time, but whether a similar pattern of improvement is observed in diabetic kidney transplant recipients remained uncertain. We aimed to compare patient outcomes between diabetic and non-diabetic transplant recipients, and to determine the effect of age and era on patient survival. METHODS: This population cohort study included all primary kidney-only transplant recipients included in the Australia and New Zealand Dialysis and Transplant registry between Jan 1, 1994, and Dec 31, 2012. The primary outcomes were all-cause mortality and death with functioning graft. Associations between outcomes and diabetes status were examined using adjusted Cox regression, and interactions between diabetes status and transplant era and recipient age were examined. FINDINGS: Of 10 714 transplant recipients, 985 (9%) had type 2 diabetes. Mortality rates in the first 10 years after transplantation were higher in recipients with diabetes (25·3 per 100 recipients) compared to those without diabetes (11·5 per 100 recipients). Compared with recipients without diabetes, the adjusted hazard ratios (HR) for all-cause mortality and death with a functioning graft in recipients with diabetes were 1·60 (95% CI 1·37-1·86; p<0·0001) and 1·54 (1·28-1·85 p<0·0001), respectively. The association between diabetes status, all-cause mortality, and death with a functioning graft was modified by recipient age (pinteraction<0·0001), with the highest risk in recipients with diabetes aged younger than 40 years (adjusted HR 5·16 [95% CI 2·84-9·35], p<0·0001; and 9·83 [4·51-21·43], p<0·0001; for all-cause mortality and death with a functioning graft, respectively). Risk was increased to a lesser extent in recipients with diabetes aged older than 55 years (adjusted HR 1·41 [95% CI 1·17-1·71; p=0·002] and 1·27 [1·02-1·59; p=0·03], for all-cause mortality and death with a functioning graft, respectively). Transplant era did not modify the association between diabetes status and mortality. INTERPRETATION: Kidney transplant recipients with type 2 diabetes had substantially poorer patient survival, with 5-year mortality rates exceeding those for non-diabetic recipients by over two times. The magnitude of this survival disadvantage was greatest in recipients with diabetes aged less than 40 years. By contrast with the general population, there was no evidence of improvement in mortality over time among people with type 2 diabetes following kidney transplantation. FUNDING: None.